Fabrication of Multiple-Channel Electrochemical Microneedle Electrode Array via Separated Functionalization and Assembly Method.

Real-time monitoring of physiological indicators inside the body is pivotal for contemporary diagnostics and treatments. Implantable electrodes can not only track specific biomarkers but also facilitate therapeutic interventions. By modifying biometric components, implantable electrodes enable in situ metabolite detection in living tissues, notably beneficial in invasive glucose monitoring, which effectively alleviates the self-blood-glucose-managing burden for patients. However, the development of implantable electrochemical electrodes, especially multi-channel sensing devices, still faces challenges: (1) The complexity of direct preparation hinders functionalized or multi-parameter sensing on a small scale. (2) The fine structure of individual electrodes results in low spatial resolution for sensor functionalization. (3) There is limited conductivity due to simple device structures and weakly conductive electrode materials (such as silicon or polymers). To address these challenges, we developed multiple-channel electrochemical microneedle electrode arrays (MCEMEAs) via a separated functionalization and assembly process. Two-dimensional microneedle (2dMN)-based and one-dimensional microneedle (1dMN)-based electrodes were prepared by laser patterning, which were then modified as sensing electrodes by electrochemical deposition and glucose oxidase decoration to achieve separated functionalization and reduce mutual interference. The electrodes were then assembled into 2dMN- and 1dMN-based multi-channel electrochemical arrays (MCEAs), respectively, to avoid damaging functionalized coatings. In vitro and in vivo results demonstrated that the as-prepared MCEAs exhibit excellent transdermal capability, detection sensitivity, selectivity, and reproducibility, which was capable of real-time, in situ glucose concentration monitoring.

N-Type polymeric mixed conductors for all-in-one aqueous electrolyte gated photoelectrochemical transistors.

An organic photoelectrochemical transistor (OPECT) is an organic electrochemical transistor (OECT) that utilizes light to toggle between ON and OFF states. The current response to light and voltage fluxes in aqueous media renders the OPECT ideal for the development of next-generation bioelectronic devices, including light-assisted biosensors, light-controlled logic gates, and artificial photoreceptors. However, existing OPECT architectures are complex, often requiring photoactive nanostructures prepared through labor-intensive synthetic methods, and despite this complexity, their performance remains limited. In this study, we develop aqueous electrolyte-compatible optoelectronic transistors using a single n-type semiconducting polymer. The n-type film performs multiple tasks: (1) gating the channel, (2) generating a photovoltage in response to light, and (3) coupling and transporting cations and electrons in the channel. We systematically investigate the photoelectrochemical properties of a range of n-type polymeric mixed conductors to understand the material requirements for maximizing phototransistor performance. Our findings contribute to the identification of crucial material and device properties necessary for constructing high-performance OPECTs with simplified design features and a direct interface with biological systems.

Mixing Insulating Commodity Polymers with Semiconducting n-type Polymers Enables High-Performance Electrochemical Transistors.

Diluting organic semiconductors with a host insulating polymer is used to increase the electronic mobility in organic electronic devices, such as thin film transistors, while considerably reducing material costs. In contrast to organic electronics, bioelectronic devices such as the organic electrochemical transistor (OECT) rely on both electronic and ionic mobility for efficient operation, making it challenging to integrate hydrophobic polymers as the predominant blend component. This work shows that diluting the n-type conjugated polymer p(N-T) with high molecular weight polystyrene (10 KDa) leads to OECTs with over three times better mobility-volumetric capacitance product (µC*) with respect to the pristine p(N-T) (from 4.3 to 13.4 F V-1 cm-1 s-1) while drastically decreasing the amount of conjugated polymer (six times less). This improvement in µC* is due to a dramatic increase in electronic mobility by two orders of magnitude, from 0.059 to 1.3 cm2 V-1 s-1 for p(N-T):Polystyrene 10 KDa 1:6. Moreover, devices made with this polymer blend show better stability, retaining 77% of the initial drain current after 60 minutes operation in contrast to 12% for pristine p(N-T). These results open a new generation of low-cost organic mixed ionic-electronic conductors where the bulk of the film is made by a commodity polymer.

Ultrasoft and High-Adhesion Block Copolymers for Neuromorphic Computing.

The "von Neumann bottleneck" is a formidable challenge in conventional computing, driving exploration into artificial synapses. Organic semiconductor materials show promise but are hindered by issues such as poor adhesion and a high elastic modulus. Here, we combine polyisoindigo-bithiophene (PIID-2T) with grafted poly(dimethylsiloxane) (PDMS) to synthesize the triblock-conjugated polymer (PIID-2T-PDMS). The polymer exhibited substantial enhancements in adhesion (4.8-68.8 nN) and reductions in elastic modulus (1.6-0.58 GPa) while maintaining the electrical characteristics of PIID-2T. The three-terminal organic synaptic transistor (three-terminal p-type organic artificial synapse (TPOAS)), constructed using PIID-2T-PDMS, exhibits an unprecedented analog switching range of 276×, surpassing previous records, and a remarkable memory on-off ratio of 106. Moreover, the device displays outstanding operational stability, retaining 99.6% of its original current after 1600 write-read events in the air. Notably, TPOAS replicates key biological synaptic behaviors, including paired-pulse facilitation (PPF), short-term plasticity (STP), and long-term plasticity (LTP). Simulations using handwritten digital data sets reveal an impressive recognition accuracy of 91.7%. This study presents a polyisoindigo-bithiophene-based block copolymer that offers enhanced adhesion, reduced elastic modulus, and high-performance artificial synapses, paving the way for the next generation of neuromorphic computing systems.

Integrated electronic/fluidic microneedle system for glucose sensing and insulin delivery.

Background: Precise and dynamic blood glucose regulation is paramount for both diagnosing and managing diabetes. Continuous glucose monitoring (CGM) coupled with insulin pumps forms an artificial pancreas, enabling closed-loop control of blood glucose levels. Indeed, this integration necessitates advanced micro-nano fabrication techniques to miniaturize and combine sensing and delivery modules on a single electrode. While microneedle technology can mitigate discomfort, concerns remain regarding infection risk and potential sensitivity limitations due to their short needle length. Methods: This study presents the development of an integrated electronic/fluidic microneedle patch (IEFMN) designed for both glucose sensing and insulin delivery. The use of minimally invasive microneedles mitigates nerve contact and reduces infection risks. The incorporation of wired enzymes addresses the issue of "oxygen deprivation" during glucose detection by decreasing the reliance on oxygen. The glucose-sensing electrodes employ wired enzyme functionalization to achieve lower operating voltages and enhanced resilience to sensor interference. The hollow microneedles' inner channel facilitates precise drug delivery for blood glucose regulation. Results: Our IEFMN-based system demonstrated high sensitivity, selectivity, and a wide response range in glucose detection at relatively low voltages. This effectively reduced interference from both external and internal active substances. The microneedle array ensured painless and minimally invasive skin penetration, while wired enzyme functionalization not only lowered sensing potential but also improved glucose detection accuracy. In vivo, experiments conducted in rats showed that the device could track subcutaneous glucose fluctuations in real-time and deliver insulin to regulate blood glucose levels. Conclusions: Our work suggests that the IEFMN-based system, developed for glucose sensing and insulin delivery, exhibits good performance during in vivo glucose detection and drug delivery. It holds the potential to contribute to real-time, intelligent, and controllable diabetes management.

Cleanroom-Free Direct Laser Micropatterning of Polymers for Organic Electrochemical Transistors in Logic Circuits and Glucose Biosensors.

Organic electrochemical transistors (OECTs) are promising devices for bioelectronics, such as biosensors. However, current cleanroom-based microfabrication of OECTs hinders fast prototyping and widespread adoption of this technology for low-volume, low-cost applications. To address this limitation, a versatile and scalable approach for ultrafast laser microfabrication of OECTs is herein reported, where a femtosecond laser to pattern insulating polymers (such as parylene C or polyimide) is first used, exposing the underlying metal electrodes serving as transistor terminals (source, drain, or gate). After the first patterning step, conducting polymers, such as poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS), or semiconducting polymers, are spin-coated on the device surface. Another femtosecond laser patterning step subsequently defines the active polymer area contributing to the OECT performance by disconnecting the channel and gate from the surrounding spin-coated film. The effective OECT width can be defined with high resolution (down to 2 µm) in less than a second of exposure. Micropatterning the OECT channel area significantly improved the transistor switching performance in the case of PEDOT:PSS-based transistors, speeding up the devices by two orders of magnitude. The utility of this OECT manufacturing approach is demonstrated by fabricating complementary logic (inverters) and glucose biosensors, thereby showing its potential to accelerate OECT research.

Versatile Neuromorphic Modulation and Biosensing based on N-type Small-molecule Organic Mixed Ionic-Electronic Conductors.

The ion/chemical-based modulation feature of organic mixed ionic-electronic conductors (OMIECs) are critical to advancing next generation bio-integrated neuromorphic hardware. Despite achievements with polymeric OMIECs in organic electrochemical neuronal synapse (OENS). However, small molecule OMIECs based OENS has not yet been realized. Here, for the first time, we demonstrate an effective materials design concept of combining n-type fused all-acceptor small molecule OMIECs with subtle side chain optimization that enables robustly and flexibly modulating versatile synaptic behavior and sensing neurotransmitter in solid or aqueous electrolyte, operating in accumulation modes. By judicious tuning the ending side chains, the linear oligoether and butyl chain derivative gNR-Bu exhibits higher recognition accuracy for a model artificial neural network (ANN) simulation, higher steady conductance states and more outstanding ambient stability, which is superior to the state-of-art n-type OMIECs based OENS. These superior artificial synapse characteristics of gNR-Bu can be attributed to its higher crystallinity with stronger ion bonding capacities. More impressively, we unprecedentedly realized n-type small-molecule OMIECs based OENS as a neuromorphic biosensor enabling to respond synaptic communication signals of dopamine even at sub-µM level in aqueous electrolyte. This work may open a new path of small-molecule ion-electron conductors for next-generation ANN and bioelectronics.

Aldol Condensation for the Construction of Organic Functional Materials.

Aldol condensation is a cost-effective and sustainable synthetic method, offering the advantages of low complexity, substrate universality, and high efficiency. Over the past decade, it has become popular for creating next-generation organic functional materials, particularly rigid-rod conjugated (semi)conductors. This review focuses on conjugated small molecules, oligomers, and polymeric (semi)conductors synthesized through aldol condensation, with emphasis on their remarkable features in advancing n-type organic field-effect transistors (OFETs), organic electrochemical transistors (OECTs), organic photovoltaics (OPVs), and organic thermoelectrics (OTEs) as well as NIR-II photothermal conversion. Coherence character, optical properties, microstructure, and chain conformation are investigated to understand material-property relationships. Future applications and challenges in this area are also discussed.

Mindfulness-based therapy improves brain functional network reconfiguration efficiency.

Mindfulness-based interventions are showing increasing promise as a treatment for psychological disorders, with improvements in cognition and emotion regulation after intervention. Understanding the changes in functional brain activity and neural plasticity that underlie these benefits from mindfulness interventions is thus of interest in current neuroimaging research. Previous studies have found functional brain changes during resting and task states to be associated with mindfulness both cross-sectionally and longitudinally, particularly in the executive control, default mode and salience networks. However, limited research has combined information from rest and task to study mindfulness-related functional changes in the brain, particularly in the context of intervention studies with active controls. Recent work has found that the reconfiguration efficiency of brain activity patterns between rest and task states is behaviorally relevant in healthy young adults. Thus, we applied this measure to investigate how mindfulness intervention changed functional reconfiguration between rest and a breath-counting task in elderly participants with self-reported sleep difficulties. Improving on previous longitudinal designs, we compared the intervention effects of a mindfulness-based therapy to an active control (sleep hygiene) intervention. We found that mindfulness intervention improved self-reported mindfulness measures and brain functional reconfiguration efficiency in the executive control, default mode and salience networks, though the brain and behavioral changes were not associated with each other. Our findings suggest that neuroplasticity may be induced through regular mindfulness practice, thus bringing the intrinsic functional configuration in participants' brains closer to a state required for mindful awareness.

3D-Printed Intrinsically Stretchable Organic Electrochemical Synaptic Transistor Array.

Organic electrochemical transistors (OECTs) for skin-like bioelectronics require mechanical stretchability, softness, and cost-effective large-scale manufacturing. However, developing intrinsically stretchable OECTs using a simple and fast-response technique is challenging due to limitations in functional materials, substrate wettability, and integrated processing of multiple materials. In this regard, we propose a fabrication method devised by combining the preparation of a microstructured hydrophilic substrate, multi-material printing of functional inks with varying viscosities, and optimization of the device channel geometries. The resulting intrinsically stretchable OECT array with synaptic properties was successfully manufactured. These devices demonstrated high transconductance (22.5 mS), excellent mechanical softness (Young's modulus ∼ 2.2 MPa), and stretchability (∼30%). Notably, the device also exhibited artificial synapse functionality, mimicking the biological synapse with features such as paired-pulse depression, short-term plasticity, and long-term plasticity. This study showcases a promising strategy for fabricating intrinsically stretchable OECTs and provides valuable insights for the development of brain-computer interfaces.

Organic Electrochemical Transistor Based on Hydrophobic Polymer Tuned by Ionic Gels.

Hydrophobic conjugated polymers have poor ionic transport property, so hydrophilic side chains are often grafted for their application as organic electrochemical transistors (OECTs). However, this modification lowers their charge transport ability. Here, an ionic gel interfacial layer is applied to improve the ionic transport while retaining the charge transport ability of the polymers. By using the ionic gels comprising gel matrix and ionic liquids as the interfacial layers, the hydrophobic polymer achieves the OECT feature with high transconductance, low threshold voltage, high current on/off ratio, short switching time, and high operational stability. The working mechanism is also revealed. Moreover, the OECT performance can be tuned by varying the types and ratios of ionic gels. With the proposed ionic gel strategy, OECTs can be effectively realized with hydrophobic conjugated polymers.

Tunable control of the performance of aqueous-based electrochemical devices by post-polymerization functionalization.

Functionalized polymeric mixed ionic-electronic conductors (PMIECs) are highly desired for the development of electrochemical applications, yet are hindered by the limited conventional synthesis techniques. Here, we propose a "graft-onto-polymer" synthesis strategy by post-polymerization functionalization (GOP-PPF) to prepare a family of PMIECs sharing the same backbone while functionalized with varying ethylene glycol (EG) compositions (two, four, and six EG repeating units). Unlike the typical procedure, GOP-PPF uses a nucleophilic aromatic substitution reaction for the facile and versatile attachment of functional units to a pre-synthesized conjugated-polymer precursor. Importantly, these redox-active PMIECs are investigated as a platform for energy storage devices and organic electrochemical transistors (OECTs) in aqueous media. The ion diffusivity, charge mobility and charge-storage capacity can be significantly improved by optimizing the EG composition. Specifically, g2T2-gBT6 containing the highest EG density gives the highest charge-storage capacity exceeding 180 F g-1 among the polymer series, resulting from the improved ion diffusivity. Moreover, g2T2-gBT4 with four EG repeating units exhibits a superior performance compared to its two analogues in OECTs, associated with a high µC* up to 359 F V-1 cm-1 s-1, owing to the optimal balance between ionic-electronic coupling and charge mobility. Through the GOP-PPF, PMIECs can be tailored to access desirable performance metrics at the molecular level.

Population-level health and economic impacts of introducing Vaccae vaccination in China: a modelling study.

INTRODUCTION: Given the ageing epidemic of tuberculosis (TB), China is facing an unprecedented opportunity provided by the first clinically approved next-generation TB vaccine Vaccae, which demonstrated 54.7% efficacy for preventing reactivation from latent infection in a phase III trial. We aim to assess the population-level health and economic impacts of introducing Vaccae vaccination to inform policy-makers. METHODS: We evaluated a potential national Vaccae vaccination programme in China initiated in 2024, assuming 20 years of protection, 90% coverage and US$30/dose government contract price. An age-structured compartmental model was adapted to simulate three strategies: (1) no Vaccae; (2) mass vaccination among people aged 15-74 years and (3) targeted vaccination among older adults (60 years). Cost analyses were conducted from the healthcare sector perspective, discounted at 3%. RESULTS: Considering postinfection efficacy, targeted vaccination modestly reduced TB burden (~20%), preventing cumulative 8.01 (95% CI 5.82 to 11.8) million TB cases and 0.20 (0.17 to 0.26) million deaths over 2024-2050, at incremental cost-effectiveness ratio of US$4387 (2218 to 10 085) per disability adjusted life year averted. The implementation would require a total budget of US$22.5 (17.6 to 43.4) billion. In contrast, mass vaccination had a larger bigger impact on the TB epidemic, but the overall costs remained high. Although both preinfection and postinfection vaccine efficacy type might have a maximum impact (>40% incidence rate reduction in 2050), it is important that the vaccine price does not exceed US$5/dose. CONCLUSION: Vaccae represents a robust and cost-effective choice for TB epidemic control in China. This study may facilitate the practice of evidence-based strategy plans for TB vaccination and reimbursement decision making.

Highly Efficient Mixed Conduction in a Fused Oligomer n-Type Organic Semiconductor Enabled by 3D Transport Pathways.

Tailoring organic semiconductors to facilitate mixed conduction of ionic and electronic charges when interfaced with an aqueous media has spurred many recent advances in organic bioelectronics. The field is still restricted, however, by very few n-type (electron-transporting) organic semiconductors with adequate performance metrics. Here, a new electron-deficient, fused polycyclic aromatic system, TNR, is reported with excellent n-type mixed conduction properties including a µC* figure-of-merit value exceeding 30 F cm-1 V-1 s-1 for the best performing derivative. Comprising three naphthalene bis-isatin moieties, this new molecular design builds on successful small-molecule mixed conductors; by extending the molecular scaffold into the oligomer domain, good film-forming properties, strong π-π interactions, and consequently excellent charge-transport properties are obtained. Through judicious optimization of the side chains, the linear oligoether and branched alkyl chain derivative bgTNR is obtained which shows superior mixed conduction in an organic electrochemical transistor configuration including an electron mobility around 0.3 cm2 V-1 s-1 . By optimizing the side chains, the dominant molecular packing can be changed from a preferential edge-on orientation (with high charge-transport anisotropy) to an oblique orientation that can support 3D transport pathways which in turn ensure highly efficient mixed conduction properties across the bulk semiconductor film.

Electron-Deficient Polycyclic Molecules via Ring Fusion for n-Type Organic Electrochemical Transistors.

The primary challenge for n-type small-molecule organic electrochemical transistors (OECTs) is to improve their electron mobilities and thus the key figure of merit µC*. Nevertheless, few reports in OECTs have specially proposed to address this issue. Herein, we report a 10-ring-fused polycyclic π-system consisting of the core of naphthalene bis-isatin dimer and the terminal moieties of rhodanine, which features intramolecular noncovalent interactions, high π-delocalization and strong electron-deficient characteristics. We find that this extended π-conjugated system using the ring fusion strategy displays improved electron mobilities up to 0.043 cm2 V-1 s-1 compared to our previously reported small molecule gNR, and thereby leads to a remarkable µC* of 10.3 F cm-1 V-1 s-1 in n-type OECTs, which is the highest value reported to date for small-molecule OECTs. This work highlights the importance of π-conjugation extension in polycyclic-fused molecules for enhancing the performance of n-type small-molecule OECTs.

Backbone coplanarity manipulation via hydrogen bonding to boost the n-type performance of polymeric mixed conductors operating in aqueous electrolyte.

The development of high-performance n-type semiconducting polymers remains a significant challenge. Reported here is the construction of a coplanar backbone via intramolecular hydrogen bonds to dramatically enhance the performance of n-type polymeric mixed conductors operating in aqueous electrolyte. Specifically, glycolated naphthalene tetracarboxylicdiimide (gNDI) couples with vinylene and thiophene to give gNDI-V and gNDI-T, respectively. The hydrogen bonding functionalities are fused to the backbone to ensure a more coplanar backbone and much tighter π-π stacking of gNDI-V than gNDI-T, which is evidenced by density functional theory simulations and grazing-incidence wide-angle X-ray scattering. Importantly, these copolymers are fabricated as the active layer of the aqueous-based electrochromic devices and organic electrochemical transistors (OECTs). gNDI-V exhibits a larger electrochromic contrast (ΔT = 30%) and a higher coloration efficiency (1988 cm2 C-1) than gNDI-T owing to its more efficient ionic-electronic coupling. Moreover, gNDI-V gives the highest electron mobility (0.014 cm2 V-1 s-1) and µC* (2.31 FV-1 cm-1 s-1) reported to date for NDI-based copolymers in OECTs, attributed to the improved thin-film crystallinity and molecular packing promoted by hydrogen bonds. Overall, this work marks a remarkable advance in the n-type polymeric mixed conductors and the hydrogen bond functionalization strategy opens up an avenue to access desirable performance metrics for aqueous-based electrochemical devices.

Enhancing the Performance of N-Type Thermoelectric Devices via Tuning the Crystallinity of Small Molecule Semiconductors.

In the development of high-performance organic thermoelectric devices, n-type materials, especially with small molecule semiconductors, lags far behind p-type materials. In this paper, three small molecules are synthesized based on electron-deficient naphthalene bis-isatin building blocks bearing different alkyl chains with the terminal functionalized with 3-ethylrhodanine unit and studied their aggregation and doping mechanism in detail. It is found that crystallinity plays an essential role in tuning the doping behavior of small molecules. Molecules with too strong crystallinity tend to aggregate with each other to form large crystalline domains, which cause significant performance degradation. While molecules with weak crystallinity can tolerate more dopants, most of them exhibit low mobility. By tuning the crystallinity carefully, organic thermoelectric devices based on C12NR can maintain high mobility and realize effective doping simultaneously, and a high power factor of 1.07 µW m-1 K-2 at 100 °C is realized. This delicate molecular design by modulating crystallinity provides a new avenue for realizing high-performance organic thermoelectric devices.

Effects and mechanisms of total flavones of Abelmoschus manihot in attenuating diabetic tubulopathy by targeting endoplasmic reticulum stress-induced cell apoptosis / 中国中药杂志

Renal tubular injury in patients with diabetic kidney disease(DKD) may be accompanied by glomerular and microvascular diseases. It plays a critical role in the progression of renal damage in DKD, and is now known as diabetic tubulopathy(DT). To explore the multi-targeted therapeutic effects and pharmacological mechanisms in vivo of total flavones of Abelmoschus manihot(TFA), an extract from traditional Chinese medicine for treating kidney disease, in attenuating DT, the authors randomly divided all rats into four groups: a normal control group(normal group), a DT model group(model group), a DT model+TFA-treated group(TFA group) and a DT model+rosiglitazone(ROS)-treated group(ROS group). The DT rat model was established based on the DKD rat model by means of integrated measures. After successful modeling, the rats in the four groups were continuously given double-distilled water, TFA suspension, and ROS suspension, respectively by gavage every day. After 6 weeks of treatment, all rats were sacrificed, and the samples of their urine, blood, and kidneys were collected. The effects of TFA and ROS on various indicators related to urine and blood biochemistry, renal tubular injury, renal tubular epithelial cell apoptosis and endoplasmic reticulum stress(ERS), as well as the activation of the protein kinase R-like endoplasmic reticulum kinase(PERK)-eukaryotic translation initiation factor 2α(eIF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP) signaling pathway in the kidney of the DT model rats were investigated. The results indicated that hypertrophy of renal tubular epithelial cells, renal tubular hyperplasia and occlusion, as well as interstitial extracellular matrix and collagen deposition occurred in the DT model rats. Moreover, significant changes were found in the expression degree and the protein expression level of renal tubular injury markers. In addition, there was an abnormal increase in tubular urine proteins. After TFA or ROS treatment, urine protein, the characteristics of renal tubular injury, renal tubular epithelial cell apoptosis and ERS, as well as the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in the kidney of the DT model rats were improved to varying degrees. Therein, TFA was superior to ROS in affecting the pathological changes in renal tubule/interstitium. In short, with the DT model rats, this study demonstrated that TFA could attenuate DT by multiple targets through inhibiting renal tubular ERS-induced cell apoptosis in vivo, and its effect and mechanism were related to suppressing the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in the kidney. These findings provided preliminary pharmacological evidence for the application of TFA in the clinical treatment of DT.

Effects and mechanisms of total flavones of Abelmoschus manihot in improving insulin resistance and podocyte epithelial-mesenchymal transition in diabetic kidney disease based on IRS1/PI3K/Akt pathway / 中国中药杂志

This study aimed to explore the effects and mechanisms of total flavones of Abelmoschus manihot(TFA), the extracts from traditional Chinese medicine indicated for kidney diseases, on insulin resistance(IR) and podocyte epithelial-mesenchymal transition(EMT) in diabetic kidney disease(DKD), and further to reveal the scientific connotation. Thirty-two rats were randomly divided into a normal group, a model group, a TFA group, and a rosiglitazone(ROS) group. The modified DKD model was induced in rats by methods including high-fat diet feeding, unilateral nephrectomy, and streptozotocin(STZ) intraperitoneal injection. After modeling, the rats in the four groups were given double-distilled water, TFA suspension, and ROS suspension correspondingly by gavage every day. At the end of the 8th week of drug administration, all rats were sacrificed, and the samples of urine, blood, and kidney tissues were collected. The parameters and indicators related to IR and podocyte EMT in the DKD model rats were examined and observed, including the general condition, body weight(BW) and kidney weight(KW), the biochemical parameters and IR indicators, the protein expression levels of the key signaling molecules and structural molecules of slit diaphragm in the renal insulin receptor substrate(IRS) 1/phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(Akt) pathway, foot process form and glomerular basement membrane(GBM) thickness, the expression of the marked molecules and structural molecules of slit diaphragm in podocyte EMT, and glomerular histomorphological characteristics. The results showed that for the DKD model rats, both TFA and ROS could improve the general condition, some biochemical parameters, renal appearance, and KW. The ameliorative effects of TFA and ROS were equivalent on BW, urinary albumin(UAlb)/urinary creatinine(UCr), serum creatinine(Scr), triglyceride(TG), and KW. Secondly, they could both improve IR indicators, and ROS was superior to TFA in improving fast insulin(FIN) and homeostasis model assessment of insulin resistance(HOMA-IR). Thirdly, they could both improve the protein expression levels of the key signaling molecules in the IRS1/PI3K/Akt pathway and glomerulosclerosis in varying degrees, and their ameliorative effects were similar. Finally, both could improve podocyte injury and EMT, and TFA was superior to ROS. In conclusion, this study suggested that podocyte EMT and glomerulosclerosis could be induced by IR and the decreased activation of the IRS1/PI3K/Akt pathway in the kidney in DKD. Similar to ROS, the effects of TFA in inhibiting podocyte EMT in DKD were related to inducing the activation of the IRS1/PI3K/Akt pathway and improving IR, which could be one of the scientific connotations of TFA against DKD. This study provides preliminary pharmacological evidence for the development and application of TFA in the field of diabetic complications.

MF-SuP-pKa: Multi-fidelity modeling with subgraph pooling mechanism for pKa prediction

Acid-base dissociation constant (pKa) is a key physicochemical parameter in chemical science, especially in organic synthesis and drug discovery. Current methodologies for pKa prediction still suffer from limited applicability domain and lack of chemical insight. Here we present MF-SuP-pKa (multi-fidelity modeling with subgraph pooling for pKa prediction), a novel pKa prediction model that utilizes subgraph pooling, multi-fidelity learning and data augmentation. In our model, a knowledge-aware subgraph pooling strategy was designed to capture the local and global environments around the ionization sites for micro-pKa prediction. To overcome the scarcity of accurate pKa data, low-fidelity data (computational pKa) was used to fit the high-fidelity data (experimental pKa) through transfer learning. The final MF-SuP-pKa model was constructed by pre-training on the augmented ChEMBL data set and fine-tuning on the DataWarrior data set. Extensive evaluation on the DataWarrior data set and three benchmark data sets shows that MF-SuP-pKa achieves superior performances to the state-of-the-art pKa prediction models while requires much less high-fidelity training data. Compared with Attentive FP, MF-SuP-pKa achieves 23.83% and 20.12% improvement in terms of mean absolute error (MAE) on the acidic and basic sets, respectively.